We have recently discovered a novel intracellular signal transduction pathway involved in the regulation of radiation sensitivity in mammals. This pathway is mediated by the elongation factor 2 kinase (eEF2K), a key regulator of global protein synthesis. We found that inactivation of this pathway in mice can confer resistance to the lethal effects of gamma radiation and protects mice from hair graying caused by radiation. We investigated the role of eEF2 kinase in radiation sensitivity of gastrointestinal tract and we found that inactivation of eEF2 kinase protects cells in the intestine from the radiation-induced cell death. The goal of this proposal is to further characterize this novel signal transduction pathway and to develop approaches that can be used to protect tissues particularly of gastrointestinal tract from radiation damage in humans exposed to terrorist or accidental radiological or nuclear attack. There are the following specific aims in this proposal. 1. To characterize a novel signal transduction pathway involving eEF2 kinase that modulates apoptosis and radiation sensitivity. 2. To identify specific inhibitors of eEF2 kinase and to develop lead compounds that can be used to develop drugs that protect gastrointestinal tract from radiation damage.